Stable pharmaceutical products

ABSTRACT

Provided herein is a stable pharmaceutical product comprising a dry powder inhalation device, and a pharmaceutical composition that comprises R,R-Formoterol L-tartrate salt, in particular crystalline R,R-formoterol L-tartrate; and ciclesonide.

FIELD OF THE INVENTION

The present invention relates to stable pharmaceutical productscomprising a dry powder inhalation device, and a pharmaceuticalcomposition within the device comprising R,R-formoterol L-tartrate salt,and in particular crystalline R,R-formoterol L-tartrate salt, as well asmethods of making such products. More particularly, the presentinvention relates to pharmaceutical products having a pharmaceuticalcomposition within a dry powder inhalation device comprisingR,R-Formoterol L-tartrate salt, particularly crystalline R,R-formoterolL-tartrate salt, and ciclesonide, wherein the pharmaceutical compositionis stable in the presence of a substance that could leach from acomponent of the device and induce R,R-formoterol L-tartrate salt, andin particular crystalline R,R-formoterol L-tartrate degradation.

BACKGROUND OF THE INVENTION

Formoterol, (+/−)N-[2-hydroxy-5-[1-hydroxy-2[[2-(p-methoxyphenyl)-2-propyl]amino]ethyl]phenyl]-formamide, is ahighly potent long lasting bronchodilator when inhaled. Formoterol hastwo chiral centers in the molecule, each of which can exist in twopossible configurations. Thus, formoterol has four stereoisomers: (R,R),(S,S), (R,S) and (S,R). The racemic mixture that is commerciallyavailable for administration is a dihydrate of the fumarate salt. Theorder of potency of the isomers is (R,R)>>(R,S)=(S,R)>(S,S), and the(R,R)-isomer is 1000-fold more potent than the (S,S)-isomer.Administration of the pure (R,R)-isomer also offers an improvedtherapeutic ratio. U.S. Pat. No. 6,268,533 and PCT application WO00/21487 disclose that the L-(+)-tartrate salt of R,R-formoterol isunexpectedly superior to other salts of R,R-formoterol, being easy tohandle, pharmaceutically innocuous and non-hygroscopic. Also, U.S. Pat.No. 6,268,533 and U.S. Pat. No. 6,472,563, which are hereby incorporatedby reference herein in their entireties, disclose that the L-tartratesalt of R,R-formoterol exists in three polymorphic forms, polymorph (A),(B), and (C).

Formoterol drug substances are known to be stable at ambient conditionsfor up to two years. However, when R,R-formoterol L-tartrate salt ismixed with lactose, degradation is known to occur (Maillards reaction)because of interactions between the amino groups within theR,R-formoterol L-tartrate salt molecule and the lactose moiety.

Dry powder inhalation devices usually need to be packed in asubstantially impermeable package to prevent atmospheric moistureingress. The use of such impermeable packages may cause accumulation ofcertain trace substances within the sealed local environment to a levelsufficient for them to interact with the pharmaceutical compositioncontained in the dry powder inhalation device. Such interaction, forexample, may result in an adduct between the pharmaceutical compositionand the trace substance, resulting in the formation of degradationproducts. For instance, a dry powder inhaler generally includes a numberof plastic components molded from an acetal homopolymer, and the plasticcomponents may contain trace formaldehyde formed as a breakdown productduring the molding of acetal resins. It is believed that the traceformaldehyde released from the plastic components is capable of formingan adduct with various pharmaceutical compositions when packaged withina substantially impermeable container.

Accordingly, what is needed is a stable pharmaceutical productcomprising R,R-formoterol L-tartrate salt, and in particular crystallineR,R-formoterol L-tartrate salt, in a dry powder inhalation device,wherein the degradation of R,R-formoterol L-tartrate salt is reduced oreliminated.

The citation of any reference herein should not be construed as anadmission that such reference is available as “Prior Art” to the instantapplication.

SUMMARY OF THE INVENTION

Provided herein is a novel and useful stable pharmaceutical product inwhich the degradation of R,R formoterol L-tartrate salt, and inparticular crystalline R,R-formoterol L-tartrate salt, due tointeraction with a substance that leaches from a component of a drypowder inhalation device of the stable pharmaceutical product, or as aresult of a Maillard reaction between R,R formoterol L-tartrate salt,particularly crystalline R,R-formoterol L-tartrate salt, and apharmaceutically acceptable carrier, e.g. a reducing sugar, is reducedor eliminated.

Broadly, the present invention extends to a stable pharmaceuticalproduct that comprises a dry powder inhalation device, an effectiveamount of a sorbent material, a pharmaceutical composition within thedevice that comprises (i) crystalline R,R-formoterol L-tartrate salt,and (ii) ciclesonide. A stable pharmaceutical product of the presentinvention also comprises a sealed package that forms a chamber withinwhich the dry powder inhalation device, sorbent material, andpharmaceutical composition are situated.

Moreover, the present invention extends to a stable pharmaceuticalproduct comprising a dry powder inhalation device, a porous sachetcontaining an effective amount of 10 Å molecular sieves, and apharmaceutical composition within the device, which comprisescrystalline R,R-formoterol L-tartrate salt; ciclesonide; and a reducingsugar. The device and the porous sachet are contained in a volumeenclosed by a sealed package.

The present invention also extends to a stable pharmaceutical productcomprising:

-   -   a) a dry powder inhalation device;    -   b) a porous sachet enclosing 4 grams of 10 Å molecular sieves;    -   c) a pharmaceutical composition within the device comprising:    -   (i) crystalline R,R-formoterol L-tartrate salt, wherein the        crystalline R,R-formoterol L-tartrate salt has a particle size        of about 0.1 μm to about 10 μm;    -   (ii) ciclesonide; and    -   (iii) non-micronized lactose monohydrate; and    -   d) a sealed package having an enclosed volume within which the        device, the sachet and the pharmaceutical composition are        situated.

Furthermore, in a pharmaceutical composition of a stable pharmaceuticalproduct of the present invention, the particle size of the crystallineR,R-formoterol L-tartrate salt can vary. For example, the particle sizecan be about 0.1 μm to about 10 μm. In a particular embodiment, about95% of the particles of the crystalline R,R-formoterol L-tartrate salthave a particle size less than about 5 μm.

The present invention also extends to a stable pharmaceutical product asdescribed herein, wherein the pharmaceutical composition furthercomprises a pharmaceutically acceptable carrier. Numerouspharmaceutically acceptable carriers have applications herein. Aparticular example is a reducing sugar, such as lactose, glucose,mannose, galactose, maltose, xylose, cellobiose, mellibiose,maltotriose, etc., as well as hydrates thereof. In a particularembodiment, the reducing sugar is lactose or lactose monohydrate.Moreover, a reducing sugar having applications herein as apharmaceutically acceptable carrier need not be micronised. Naturally,the particle size of a pharmaceutically acceptable carrier of a stableproduct of the present invention can vary. In an embodiment of thepresent invention comprising a pharmaceutically effective carrier, whichis a reducing sugar, the size of the particles can range from about 0.5μm to about 350 μm, from about 0.5 μm to about 315 μm, from about 0.5 μmto about 150 μm, from about 0.5 μm to about 100 μm, from about 0.5 μm toabout 45 μm, from about 0.5 μm to about 25 μm, from about 0.5 μm toabout 10 μm, from about 5 μm to about 350 μm, from about 5 μm to about315 μm, from about 5 μm to about 150 μm, from about 5 μm to about 100μm, from about 5 μm to about 45 μm, from about 5 μm to about 25 μm, fromabout 5 μm to about 10 μm, from about 10 μm to about 350 μm, from about10 μm to about 315 μm, from about 10 μm to about 150 μm, from about 10μm to about 100 μm, from about 10 μm to about 45 μm, from about 10 μm toabout 25 μm, from about 25 μm to about 350 μm, from about 25 μm to about315 μm, from about 25 μm to about 150 μm, from about 25 μm to about 100μm, from about 25 μm to about 45 μm, from about 45 μm to about 350 μm,from about 45 μm to about 315 μm, from about 45 μm to about 150 μm, fromabout 45 μm to about 100 μm, from about 100 μm to about 350 μm fromabout 100 μm to about 315 μm, from about 100 μm to about 150 μm, fromabout 150 μm to about 350 μm, from about 150 μm to about 315 μm, fromabout 315 μm to about 350 μm. In a particular embodiment, thepharmaceutically acceptable carrier is a non-micronised reducing sugar,e.g. lactose monohydrate, having particles of a mean particle size ofabout 41 μm.

The present invention further extends to a stable pharmaceutical productas described herein, wherein the ratio of pharmaceutically acceptablecarrier to R,R-formoterol L-tartrate salt, and in particular crystallineR,R-formoterol L-tartrate salt, can vary in a pharmaceutical compositionof the stable pharmaceutical product. In an embodiment of the presentinvention, the ratio is about 2969 μg to about 3016 μg ofpharmaceutically acceptable carrier per about 0.5 μg to about 4 μg ofR,R-formoterol L-tartrate salt, e.g. crystalline R,R-formoterolL-tartrate salt. In a more particular embodiment, a pharmaceuticalcomposition comprises about 2969 μg to about 3016 μg of pharmaceuticallyacceptable carrier per about 1 μg to about 2 μg of R,R-formoterolL-tartrate salt, and in particular crystalline R,R-formoterol L-tartratesalt; and in a still more particular embodiment, a pharmaceuticalcomposition comprises about 2969 μg to about 3016 μg of pharmaceuticallyacceptable carrier per about 1 μg of R,R-formoterol L-tartrate salt,more particularly crystalline R,R-formoterol L-tartrate salt.

Also, the present invention extends to a stable pharmaceutical productas described herein, wherein the sealed package is substantiallyimpermeable to moisture. Numerous materials for producing such a sealedpackage have applications in a stable pharmaceutical product of thepresent invention, e.g. metal, glass, a flexible laminate, plastic, or acombination thereof, to name only a few. In particular, a sealed packageof a stable pharmaceutical product of the present invention can be madefrom a flexible laminate comprising three layers: an inner layer, abarrier layer, and an outer layer. Numerous materials can be used forthe outer layer, including paper or a polymer, such as polyester.Likewise, the barrier layer, which is moisture impermeable, can be madeof a variety of materials, such as a polymer or a metal, e.g. aluminum,copper, steel, zinc, iron, tin, magnesium an amalgam, etc., to name onlya few. The inner layer can also be made of a variety of materials thatcan undergo heat sealing. In a particular embodiment of a stablepharmaceutical product of the present invention, the flexible laminatecomprises a 12 micron polyester outer layer, a 9 micron aluminum barrierlayer, and a 50 micron polyethylene inner layer. An adhesive holds eachlayer in place. The sealing of a package of a stable pharmaceuticalproduct can be accomplished in a variety of ways. More specifically,heat-sealing, gluing, welding, brazing, mechanical closures, mechanicalclamps, or compression can hermetically seal a sealed package of astable pharmaceutical product of the present invention.

Moreover, a sealed package of a stable pharmaceutical product of thepresent invention can be a bottle, a bag, a drum box or an irregularlyshaped container. In a particular embodiment, the sealed package is madeof plastic.

Furthermore, the present invention extends to a stable pharmaceuticalproduct as described herein, having various configurations. For example,in a stable pharmaceutical product of the present invention, the drypowder inhalation device can comprise a multi-dose reservoir thatcontains the pharmaceutical composition. Naturally though, the presentinvention also encompasses unit dose systems and capsule-containingsystems.

In addition, a component of a dry powder inhalation device of a stablepharmaceutical product of the present invention can be comprised of avariety of materials, including a polymer, e.g. polyacetal,polypropylene, polyacrylamide, polycarbonate, polyethylene,polyurethane, a copolymer, etc. Moreover, a component of a dry powderdevice of a stable pharmaceutical product of the present invention mayleach a substance capable of causing degredation of R,R-formoterolL-tartrate salt, and in particular crystalline R,R-formoterol L-tartratesalt. In a particular embodiment, at least one component of the drypowder inhalation device of a stable pharmaceutical product of thepresent invention comprises polyacetal, which leaches formaldehyde.

A stable pharmaceutical product of the present invention also comprisesan effective amount of a sorbent material. Examples of sorbent materialhaving applications herein include, but certainly are not limited tomolecular sieves, activated clays, charcoal, activated alumina, silica,zeolites, bauxites or any mixture thereof. Moreover, the sorbentmaterial can be located in various places in a stable pharmaceuticalproduct of the present invention. For example, an effective amount ofsorbent material can be housed within the dry powder inhalation device.Alternatively, the effective amount of sorbent material can beincorporated into a polymer mixture and manufactured into a component ofthe powder inhalation device. In still another example, the effectiveamount of sorbent material can be held in a porous sachet. The effectiveamount of sorbent material can also be incorporated into an adhesive, orinto plastic sheeting used in the packaging of a stable pharmaceuticalproduct of the present invention. In a particular embodiment of a stablepharmaceutical product of the present invention, the sorbent material isa 10 Å molecular sieve.

Accordingly, it is an aspect of the present invention to provide a novelstable pharmaceutical product having a pharmaceutical compositioncomprising R,R-formoterol L-tartrate salt, and in particular crystallineR,R-formoterol L-tartrate salt, and ciclesonide, wherein degradation ofR,R-formoterol L-tartrate salt, and particularly crystallineR,R-formoterol L-tartrate salt, and the formation of impurities, e.g. anadduct, arising from the interaction of the R,R-formoterol L-tartratesalt, in particular crystalline R,R-formoterol L-tartrate salt. with amaterial that leaches from a component of the device, e.g. formaldehyde,is reduced or eliminated.

This and other aspects of the present invention will be betterappreciated by reference to the following drawing and DetailedDescription.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1: Histogram summary of stability data that shows the enhancedstability of a dry powder inhaler (DPI) comprising of ciclesonide,non-micronised lactose monohydrate and crystalline R,R formoterolL-tartrate salt stored for 2 months at 40 degrees Celsius and 75%humidity compared to a DPI comprising of ciclesonide, lactosemonohydrate and R,S-formoterol fumarate dihydrate stored at the sameconditions, where in the DPI are wrapped in the presence of a molecularsieve. FIG. 1 also details the comparable stability of the DPIcomprising of ciclesonide, lactose monohydrate and crystallineR,R-formoterol L-tartrate salt when stored for 2 months at 25 degreesCelsius and 60% humidity and also at 4 degrees Celsius and ambienthumidity.

DETAILED DESCRIPTION

The present invention is based on the discovery that, surprisingly andunexpectedly, the addition of a sorbent material that adsorbs or absorbs(or a combination of both) with respect to a substance that leaches froma component of a dry powder inhalation device of a stable pharmaceuticalproduct of the present invention reduces or eliminates the formation ofadducts due to the interaction of R,R-formoterol L-tartrate salt, and inparticular crystalline R,R-formoterol L-tartrate salt, contained withina pharmaceutical composition and the substance. Thus the presentinvention extends various embodiments described below:

[1] A stable pharmaceutical product comprising:

-   -   a) a dry powder inhalation device;    -   b) an effective amount of a sorbent material;    -   c) a pharmaceutical composition within the device comprising:    -   (i) R,R-formoterol L-tartrate salt; and    -   (ii) ciclesonide; and    -   d) a sealed package having an enclosed volume within which the        device, the sorbent material and the pharmaceutical composition        are situated.        [2] The stable pharmaceutical product of Embodiment [1], wherein        the R,R-formoterol L-tartrate salt is crystalline R,R-formoterol        L-tartrate salt.        [3] The stable pharmaceutical product of either of Embodiments        [1] or [2], wherein the dry powder inhalation device comprises a        multi-dose reservoir that contains the pharmaceutical        composition.        [4] The stable pharmaceutical product of any of embodiments        [1]-[3] wherein a component of the dry powder inhalation device        leaches a substance capable of causing degradation of the        R,R-formoterol L-tartrate salt.        [5] The stable pharmaceutical product according to embodiment        [4], wherein the component of the device comprises polyacetal        material, and the substance is formaldehyde.        [6] The stable pharmaceutical product of any of embodiments        [1]-[5], wherein the dry powder inhalation device is an        “ULTRAHALER” device.        [7] The stable pharmaceutical product of any of embodiments        [1]-[6], wherein the sorbent material is housed within the dry        powder inhalation device.        [8] The stable pharmaceutical product of any of embodiments        [1]-[7], wherein the sorbent material is incorporated into a        polymer mixture and manufactured into a component of the dry        powder inhalation device.        [9] The stable pharmaceutical product of any of embodiments        [1]-[6], wherein the sorbent material is incorporated into        plastic sheeting used in packaging the dry powder inhalation        device.        [10] The stable pharmaceutical product of any of embodiments        [1]-[7], wherein the sorbent material is incorporated into an        adhesive.        [11] The stable pharmaceutical product of any of embodiments        [1]-[6], wherein the sorbent material is in a porous sachet.        [12] The stable pharmaceutical product of any of embodiments        [1]-[11], wherein the sorbent material is selected from the        group consisting of: a molecular sieve, activated clay,        charcoal, activated alumina, silica, a zeolite, a bauxite, and a        mixture thereof.        [13] The stable pharmaceutical product of any of embodiments        [1]-[12], wherein the sorbent material is 10 Å molecular sieves.        [14] The stable pharmaceutical product of any of embodiments        [1]-[13], wherein the R,R-formoterol L-tartrate salt has a        particle size of about 0.1 μm to about 10 μm.        [15] The stable pharmaceutical product of any of embodiments        [1]-[14], wherein greater than about 95% of the R,R-formoterol        L-tartrate salt has a particle size of less than about 5 μm.        [16] The stable pharmaceutical product of any of embodiments        [1]-[15], wherein the pharmaceutical composition further        comprises a pharmaceutically acceptable carrier.        [17] The stable pharmaceutical product of embodiment [16],        wherein the pharmaceutical composition comprises about 2969 μg        to about 3016 μg of the pharmaceutically acceptable carrier per        about 0.5 μg to about 4 μg of R,R-formoterol L-tartrate salt.        [18] The stable pharmaceutical product of either of embodiments        [16] or [17], wherein the pharmaceutical composition comprises        about 2969 μg to about 3016 μg of the pharmaceutically        acceptable carrier per about 1 μg to about 2 μg of        R,R-formoterol L-tartrate salt.        [19] The stable pharmaceutical product of any of embodiments        [16]-[18], wherein the pharmaceutical composition comprises        about 2969 μg to about 3016 μg of the pharmaceutically        acceptable carrier per about 1 μg of R,R-formoterol L-tartrate        salt.        [20] A stable pharmaceutical product comprising:    -   a) a dry powder inhalation device;    -   b) an effective amount of a sorbent material;    -   c) a pharmaceutical composition within the device comprising:    -   (i) crystalline R,R-formoterol L-tartrate salt; and    -   (ii) ciclesonide; and    -   d) a sealed package having an enclosed volume within which the        device, the sorbent material and the pharmaceutical composition        are situated.        [21] The stable pharmaceutical product of embodiment [20],        wherein the dry powder inhalation device comprises a multi-dose        reservoir that contains the pharmaceutical composition.        [22] The stable pharmaceutical product of either of embodiments        [20] or [21], wherein a component of the dry powder inhalation        device leaches a substance capable of causing degradation of the        crystalline R,R-formoterol L-tartrate salt.        [23] The stable pharmaceutical product according to embodiment        [22], wherein the component of the device comprises polyacetal        material, and the substance is formaldehyde.        [24] The stable pharmaceutical product of any of embodiments        [20]-[23], wherein the dry powder inhalation device is an        “ULTRAHALER” device.        [25] The stable pharmaceutical product of any of embodiments        [20]-[24], wherein the sorbent material is housed within the dry        powder inhalation device.        [26] The stable pharmaceutical product of any of embodiments        [20]-[25], wherein the sorbent material is incorporated into a        polymer mixture and manufactured into a component of the dry        powder inhalation device.        [27] The stable pharmaceutical product of any of embodiments        [20]-[24], wherein the sorbent material is incorporated into        plastic sheeting used in packaging the dry powder inhalation        device.        [28] The stable pharmaceutical product of any of embodiments        [20]-[25], wherein the sorbent material is incorporated into an        adhesive.        [29] The stable pharmaceutical product of any of embodiments        [20]-[24], wherein the sorbent material is in a porous sachet.        [30] The stable pharmaceutical product of any of embodiments        [20]-[29], wherein the sorbent material is selected from the        group consisting of: a molecular sieve, activated clay,        charcoal, activated alumina, silica, a zeolite, a bauxite, and a        mixture thereof.        [31] The stable pharmaceutical product of any of embodiments        [20]-[30], wherein the sorbent material is 10 Å molecular        sieves.        [32] The stable pharmaceutical product of any of embodiments        [20]-[31], wherein the crystalline R,R-formoterol L-tartrate        salt has a particle size of about 0.1 μm to about 10 μm.        [33] The stable pharmaceutical product of any of embodiments        [20]-[32], wherein greater than about 95% of the crystalline        R,R-formoterol L-tartrate salt has a particle size of less than        about 5 μm.        [34] The stable pharmaceutical product of any of embodiments        [20]-[33], wherein the pharmaceutical composition further        comprises a pharmaceutically acceptable carrier.        [35] A stable pharmaceutical product comprising:    -   a) a dry powder inhalation device;    -   b) an effective amount of a sorbent material;    -   c) a pharmaceutical composition within the device comprising:    -   (i) crystalline R,R-formoterol L-tartrate salt;    -   (ii) ciclesonide, and    -   (iii) a pharmaceutically acceptable carrier; and    -   d) a sealed package having an enclosed volume within which the        device, the sorbent material and the pharmaceutical composition        are situated.        [36] The stable pharmaceutical product of embodiment [35],        wherein the dry powder inhalation device comprises a multi-dose        reservoir that contains the pharmaceutical composition.        [37] The stable pharmaceutical product of either of embodiments        [35] or [36], wherein a component of the dry powder inhalation        device leaches a substance capable of causing degradation of the        crystalline R,R-formoterol L-tartrate salt.        [38] The stable pharmaceutical product according to embodiment        [37], wherein the component of the device comprises polyacetal        material, and the substance is formaldehyde.        [39] The stable pharmaceutical product of any of embodiments        [35]-[38], wherein the dry powder inhalation device is an        “ULTRAHALER” device.        [40] The stable pharmaceutical product of any of embodiments        [35]-[39], wherein the sorbent material is housed within the dry        powder inhalation device.        [41] The stable pharmaceutical product of any of embodiments        [35]-[40], wherein the sorbent material is incorporated into a        polymer mixture and manufactured into a component of the dry        powder inhalation device.        [42] The stable pharmaceutical product of any of embodiments        [35]-[40], wherein the sorbent material is incorporated into        plastic sheeting used in packaging the dry powder inhalation        device.        [43] The stable pharmaceutical product of any of embodiments        [35]-[40], wherein the sorbent material is incorporated into an        adhesive.        [44] The stable pharmaceutical product of any of embodiments        [35]-[39], wherein the sorbent material is in a porous sachet.        [45] The stable pharmaceutical product of any of embodiments        [35]-[44], wherein the sorbent material is selected from the        group consisting of: a molecular sieve, activated clay,        charcoal, activated alumina, silica, a zeolite, a bauxite, and a        mixture thereof.        [46] The stable pharmaceutical product of any of embodiments        [35]-[45], wherein the sorbent material is 10 Å molecular        sieves.        [47] The stable pharmaceutical product of any of embodiments        [35]-[46], wherein the crystalline R,R-formoterol L-tartrate        salt has a particle size of about 0.1 μm to about 10 μm.        [48] The stable pharmaceutical product of any of embodiments        [35]-[47], wherein greater than about 95% of the crystalline        R,R-formoterol L-tartrate salt has a particle size of less than        about 5 μm.        [49] The stable pharmaceutical product of any of embodiments        [16]-[19], [34]-[48], wherein the pharmaceutically acceptable        carrier is a reducing sugar.        [50] The stable pharmaceutical product of embodiment [49],        wherein the reducing sugar is not micronised.        [51] The stable pharmaceutical product of either of embodiments        [49] or [50], wherein the reducing sugar has a moan particle        size of about 41 μm.        [52] The stable pharmaceutical product of any of embodiments        [49]-[51], wherein the reducing sugar is selected from the group        consisting of lactose, glucose, mannose, galactose, maltose,        xylose, cellobiose, mellibiose, maltotriose, a hydrate of        lactose, a hydrate of glucose, a hydrate of mannose, a hydrate        of galactose, a hydrate of maltose, a hydrate of xylose, a        hydrate of cellobiose, a hydrate of mellibiose, a hydrate of        maltotriose, and a combination thereof.        [53] The pharmaceutical product of any of embodiments [49]-[52],        wherein the reducing sugar is lactose.        [54] The stable pharmaceutical product of any of embodiments        [49]-[53], wherein the reducing sugar is lactose monohydrate.        [55] The stable pharmaceutical product of any of embodiments        [34]-[54], wherein the pharmaceutical composition comprises        about 2969 μg to about 3016 μg of the pharmaceutically        acceptable carrier per about 0.5 μg to about 4 μg of crystalline        R,R-formoterol L-tartrate salt.        [56] The stable pharmaceutical product of any of embodiments        [34]-[55], wherein the pharmaceutical composition comprises        about 2969 μg to about 3016 μg of the pharmaceutically        acceptable carrier per about 1 μg to about 2 μg of crystalline        R,R-formoterol L-tartrate salt.        [57] The stable pharmaceutical product of any of Embodiments        [34]-[56], wherein the pharmaceutical composition comprises        about 2969 μg to about 3016 μg of the pharmaceutically        acceptable carrier per about 1 μg of crystalline R,R-formoterol        L-tartrate salt.        [58] The stable pharmaceutical product of any of embodiments        [34]-[57], wherein the pharmaceutically acceptable carrier is        non-micronized lactose monohydrate having a particle size of        about 41 μm.        [59] A stable pharmaceutical product comprising:    -   a) a dry powder inhalation device;    -   b) a porous sachet enclosing an effective amount of 10 Å        molecular sieves;    -   c) a pharmaceutical composition within the device comprising:    -   (i) crystalline R,R-formoterol L-tartrate salt;    -   (ii) ciclesonide; and    -   (iii) a reducing sugar; and    -   d) a sealed package having an enclosed volume within which the        device, the sachet and the pharmaceutical composition are        situated.        [60] The stable pharmaceutical product of embodiment [59],        wherein the reducing sugar is not micronised.        [61] The stable pharmaceutical product of either of embodiments        [59] or [60], wherein the reducing sugar has a mean particle        size of about 41 μm.        [62] The stable pharmaceutical product of any of embodiments        [59]-[61], wherein the reducing sugar is selected from the group        consisting of lactose, glucose, mannose, galactose, maltose,        xylose, cellobiose, mellibiose, maltotriose, a hydrate of        lactose, a hydrate of glucose, a hydrate of mannose, a hydrate        of galactose, a hydrate of maltose, a hydrate of xylose, a        hydrate of cellobiose, a hydrate of mellibiose, a hydrate of        maltotriose, and a combination thereof.        [63] The pharmaceutical product of any of embodiments [59]-[62],        wherein the reducing sugar is lactose.        [64] The stable pharmaceutical product of any of embodiments        [59]-[63], wherein the reducing sugar is lactose monohydrate.        [65] The stable pharmaceutical product of any of embodiments        [59]-[64], wherein the pharmaceutical composition comprises        about 2969 μg to about 3016 μg of the reducing sugar per about        0.5 μg to about 4 μg of crystalline R,R-formoterol L-tartrate        salt.        [66] The stable pharmaceutical product of any of embodiments        [59]-[65], wherein the pharmaceutical composition comprises        about 2969 μg to about 3016 μg of the reducing sugar per about 1        μg to about 2 μg of crystalline R,R-formoterol L-tartrate salt.        [67] The stable pharmaceutical product of any of embodiments        [59]-[66], wherein the pharmaceutical composition comprises        about 2969 μg to about 3016 μg of the reducing sugar per about 1        μg of crystalline R,R-formoterol L-tartrate salt.        [68] The stable pharmaceutical product of any of embodiments        [65]-[67], wherein the reducing sugar is non-micronized lactose        monohydrate having a particle size of about 41 μm.        [69] The stable pharmaceutical product of any of embodiments        [59]-[68], wherein the crystalline R,R-formoterol L-tartrate        salt has a particle size of about 0.1 μm to about 10 μm.        [70] The stable pharmaceutical product of any of embodiments        [59]-[68], wherein greater than about 95% of the crystalline        R,R-formoterol L-tartrate salt has a particle size of less than        about 5 μm.        [71] The stable pharmaceutical product of any of embodiments        [59]-[70], wherein the effective amount of molecular sieves is 4        g.        [72] A stable pharmaceutical product comprising:    -   a) a dry powder inhalation device;    -   b) a porous sachet enclosing 4 grams of 10 Å molecular sieves;    -   c) a pharmaceutical composition within the device comprising:    -   (i) crystalline R,R-formoterol L-tartrate salt, wherein the        crystalline R,R-formoterol L-tartrate salt has a particle size        of about 0.1 μm to about 10 μm;    -   (ii) ciclesonide; and    -   (iii) non-micronized lactose monohydrate; and    -   d) a sealed package having an enclosed volume within which the        device, the sachet and the pharmaceutical composition are        situated.        [73] The stable pharmaceutical product of embodiment [72],        wherein the pharmaceutical composition comprises about 2969 μg        to about 3016 μg of the non-micronized lactose monohydrate per        about 0.5 μg to about 4 μg of crystalline R,R-formoterol        L-tartrate salt.        [74] The stable pharmaceutical product of either of embodiments        [72]-[73], wherein the pharmaceutical composition comprises        about 2969 μg to about 3016 μg of the non-micronized lactose        monohydrate per about 1 μg to about 2 μg of crystalline        R,R-formoterol L-tartrate salt.        [75] The stable pharmaceutical product of any of embodiments        [72]-[74], wherein the pharmaceutical composition comprises        about 2969 μg to about 3016 μg of the non-micronized lactose        monohydrate per about 1 μg of crystalline R,R-formoterol        L-tartrate salt.        [76] The stable pharmaceutical product of any of embodiments        [72]-[75], wherein greater than about 95% of the crystalline        R,R-formoterol L-tartrate salt has a particle size of less than        about 5 μm.        [77] The stable pharmaceutical product of any of embodiments        [1]-[76], wherein the scaled package is substantially        impermeable to moisture.        [78] The stable pharmaceutical product of any of embodiments        [1]-[77], wherein the sealed package is made of metal, glass, or        plastic, and has a configuration selected from the group        consisting of a bottle, a bag, a drum box, and an irregularly        shaped container.        [79] The stable pharmaceutical product of any of embodiments        [1]-[78], wherein the sealed package is made of plastic.        [80] The stable pharmaceutical product of any of embodiments        [1]-[79], wherein the sealed package is a flexible laminate        comprising an inner layer, a barrier layer, and an outer layer,        wherein the barrier layer is located between the inner layer and        the outer layer.        [81] The stable pharmaceutical product of embodiment [80],        wherein the inner layer is polyethylene, the barrier layer is a        metal foil, wherein the metal is selected from the group        consisting of aluminum, copper, steel, zinc, tin, magnesium, and        an amalgam thereof, and the outer layer comprises polyester or        paper.        [82] The stable pharmaceutical product of embodiment [81],        wherein the flexible laminate comprises a 12 micron polyester        outer layer, a 9 micron aluminum foil barrier layer, and a 50        micron polyethylene inner layer.        [83] The stable pharmaceutical product of any of embodiments        [1]-[82], wherein the sealed package is hermetically sealed        using heat-sealing, glue, a weld, brazing the sealed package, a        mechanical closure or clamp, or compression of the scaled        package.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Also, various featuresof the invention that are, for brevity, described in the context of asingle embodiment, may also be provided separately or in any suitablesubcombination.

Moreover, numerous terms and phrases are used throughout the instantSpecification and Claims in accordance with the present invention.Therefore, if appearing herein, the following terms and phrases shallhave the definitions set out below.

As used herein, the term “stable” refers to a pharmaceutical compositionin a stable pharmaceutical product of the present invention that doesnot substantially decompose to form degradation products, e.g. adducts,when stored in a sealed package at about 40° C. at about 75% relativehumidity for at least 2 months.

As used herein, the term “dry powder inhalation device” refers to abreath activated device for administering a dry powder into the lungs ofa subject. More particularly, a dry powder inhalation device may have acomponent that gradually leaches a substance that can degradecrystalline R,R-formoterol L-tartrate salt, wherein the device iscontained within a sealed package. The sealed package may besubstantially impermeable so that a substance released from a componentof the dry powdered inhalation device of a stable pharmaceutical productof the present invention, e.g. formaldehyde that leaches from apolyacetal component, may accumulate in the package and/or the device.Therefore, the present invention is not limited to any specific type ofdry powder inhalation device as long as there is a potential for acomponent of the device to leach a substance, e.g. formaldehyde gas,that interacts with R,R,-formoterol L-tartrate salt, and in particularcrystalline R,R-formoterol L-tartrate salt to form adducts. Examples aredescribed infra.

As used herein, the term “component” refers to a component of a drypowder inhalation device, wherein the component releases a material thatcan induce R, R-formoterol L-tartrate salt degradation, and moreparticularly crystalline R,R-formoterol L-tartrate salt degradation. Ina particular embodiment of the present invention, at least one componentof a dry powder inhalation device comprises a polyacetal material(polyoxymethylene). Polyoxymethylene (polyacetal plastics-Trade Names:DELRIN (DuPont), ULTRAFORM (the Ultraform Co.), and HOSTAFORM (Ticona))are a group of plastics produced by polymerizing formaldehyde.Polyoxymethylene is used in toiletry and cosmetic articles as well asmedical devices such as inhalers and syringes. A number of dry powderinhalation device components are manufactured from polyacetal plasticthat is known to contain residual formaldehyde formed during the moldingprocess e.g. the “ULTRAHALER” device-Aventis Pharma Ltd, UK, and thosedevices described in U.S. Pat. No. 5,176,132 and U.S. Pat. No.5,678,538, and U.S. Provisional Patent Application No. 60/417,534.Polyacetal is readily available from a number of commercial sources, forexample Sigma-Aldrich, Milwaukee, Wis. 53201.

As used herein, the term “sealed package” refers to a container that issubstantially impermeable to moisture and to a substance released from acomponent of a dry powder inhalation device, such as formaldehydereleased from a polyacetal component. Such a package may be made ofmetal, glass, or plastic, and can have a conformation selected from thegroup consisting of bottles, bags, drum boxes, and irregularly shapedcontainers. For example, a sealed package of the present invention canbe a conventional flexible package, and its manufacturing is well knownto those of ordinary skill in the art. Generally, such a flexiblepackage can be constructed from flat reels of laminate, which are foldedor otherwise formed according to the packaging equipment technology,into a package by means of sealing and cutting. In a particularembodiment of the present invention, the sealed package is asubstantially impermeable flexible package in which are sealed a drypowder inhalation device and a sorbent material, e.g. a molecular sieve,enclosed in a porous sachet. In such an embodiment, the sealed packageis constructed from a flat reel of flexible material, which is curledaround into a long tube. The edges of the tube are heated (welded)together forming a seal. The cross seals are formed by a straight heaterbar, which clamps the laminate tube in front of and behind the packagecontents (i.e., the dry powder inhalation device and sorbent sachet). Italso cuts the continuous tube into individual packs. As a result, thereis a long continuous seal down the middle of the pack and the crossseals at both ends. Also, in another embodiment the package has asubstantially impermeable flexible package, in which a dry powderinhalation device and sorbent material are situated. The sorbentmaterial can be molded as part of one of the plastic components of thedry powder inhalation device of a pharmaceutical product of the presentinvention, or can be provided in a container that is fixed to a drypowder inhalation device.

A flexible package used in making a sealed package of the presentinvention generally comprises several layers of materials eitherco-extruded or bonded together to form an apparently single film of“laminate”. Such a film of laminate may have three layers adhesivelylaminated to each other: an inner layer, a barrier layer and an outerlayer. The inner layer forms the inside of the package (in contact withthe dry powder inhalation device) and is normally a thermoplastic layerand heat-sealable. A common material for the inner layer ispolyethylene, but other polyolefinic or cyclo-olefinic materials mayalso be used. In addition, special materials such as ionomers are alsoused for making the inner layer. A particular example of such an ionomeris “SURLYN”.

The barrier layer is situated between the inner and outer layers andprovides impermeability to the pack. Aluminum foil is commonly used forthe barrier layer, although any metal capable of being rolled into thinsheets can also be satisfactorily used. Other examples of applicablemetals include, but certainly are not limited to copper, steel, zinc,iron, tin, magnesium an amalgam, etc., to name only a few. A typicalthickness for the foil barrier layer is about 8 or 9 microns.Alternatively, the barrier layer may be a metalized film comprising tin,iron, zinc, magnesium or other metals coated by vacuum deposition orsputtering onto a polymeric sheet.

The outer layer normally provides support, impact resistance, andprotection for the barrier-layer, and generally conveys robustness tothe pack. A commonly used material for the outer layer is polyester,although another material, such as paper, may also be used.

Most flexible laminate materials for packaging are commerciallyavailable. For example, Pharmaflex Ltd., part of Alcan Inc.(Cramlington, Northumberland, England) supplies a laminate film havingthree layers: 12 micron polyester/9 micron aluminum foil/50 micronpolyethylene (product catalog LMP-F BRI/72/H1), wherein the aluminumfoil layer is between the polyester and polyethylene layers.

In addition to a flexible sealed package, other types of sealed packageshave applications in the present invention, provided they aresubstantially impermeable to moisture ingress. In general, when a sealedpackage or enclosure is impermeable or substantially impermeable tomoisture, it is also impermeable or substantially impermeable to asubstance that leaches from a component of a dry powder inhalationdevice of a pharmaceutical product of the present invention, e.g.formaldehyde gas, when a component comprises polyacetal. As explainedabove, formaldehyde has the potential to interact with R,R-formoterolL-tartrate salt, and in particular crystalline R,R-formoterol L-tartratesalt, in a dry powder inhalation device of a stable pharmaceuticalproduct of the present invention, resulting in degradation of theR,R-formoterol L-tartrate salt, and in particular crystallineR,R-formoterol L-tartrate salt, and formation of adducts.

As used herein, the term “R,R-formoterol L-artrate salt degradation”refers to any process that causes a decrease in the amount ofR,R-formoterol L-tartrate salt present a pharmaceutical composition of astable pharmaceutical product of the present invention, and inparticular causes a decrease in the amount of crystalline R,R-formoterolL-tartrate salt present in a pharmaceutical composition of a stablepharmaceutical product of the present invention. Such a processincludes, but certainly is not limited to, the reaction of formaldehydegas that leaches from a component of a dry powder inhalation device thatcomprises polyacetal, with R,R-formoterol L-tartrate salt, and inparticular crystalline R,R-formoterol L-tartrate salt, to form anadduct. Another process that contributes to degradation ofR,R-formoterol L-tartrate salt, particularly crystalline R,R-formoterolL-tartrate salt, is a Maillard reaction with a pharmaceuticallyacceptable carrier, particularly a reducing carrier, e.g. lactose.

As used herein, the term “adduct” refers to a compound formed by thereaction of R,R-formoterol L-tartrate salt, and in particularcrystalline R,R-formoterol L-tartrate salt, of a pharmaceuticalcomposition of a stable pharmaceutical product of the present inventionwith a substance that has leached from a component of a dry powderinhalation device of a stable pharmaceutical product of the presentinvention. In a particular embodiment in which the component comprisespolyacetal, the substance that leaches is formaldehyde. Although underno obligation to disclose a mechanism that results in the production ofan adduct, and certainly not intending to be bound to any hypothesis, itis believed at least two possible mechanisms are responsible for adductformation with formaldehyde. The first is direct contact between theR,R-formoterol L-tartrate salt, e.g. crystalline R,R-formoterolL-tartrate salt, and formaldehyde that has leached from a component ofthe dry powder inhalation device that comprises polyacetal, whichinherently contains residual formaldehyde. The second is a reactionbetween the R,R,-formoterol L-tartrate salt, such as crystallineR,R-formoterol L-tartrate salt, and gaseous formaldehyde within theinner local environment of the sealed package, wherein the gaseousformaldehyde has been released from the polyacetal components and hasaccumulated in the local environment to a significant level due to thesubstantial impermeability of the sealed package. The term “adduct” mayalso refer to a compound formed by the reaction of R,R-formoterolL-tartrate salt, and in particular crystalline R,R-formoterol L-tartratesalt, with a reducing sugar, i.e. a product of the Maillard Reaction.

The term “sorbent material” refers to a material that has the ability tocondense or hold molecules of other substances on its surface, or withinits inner structure. Such activities are often referred as “adsorbance”and “absorbance”, respectively. Thus, a sorbent material of the presentinvention can adsorb, absorb, or perform a combination of both. Examplesof sorbent material having applications herein include activated carbon,alumina, bauxite, charcoal, a zeolite, silica gel, a molecular sieve,activated clay, or any mixture thereof, etc. In a particular embodimentof the present invention, wherein a component of the dry powderinhalation device comprises polyacetal, the sorbent material adsorbs orabsorbs (or a combination thereof) formaldehyde that leaches from thecomponent so that the formaldehyde is unable to react withR,R-formoterol L-tartrate salt, and in particular crystallineR,R-formoterol L-tartrate salt, to form adducts.

The present invention is not limited to any specific sorbent material.Choosing a proper sorbent material, as well its effective amount for aparticular embodiment of the present invention is well within the skillof one of ordinary skill in the art, and may require, at most, theperformance of certain routine laboratory techniques. Applicants havefound that the most effective sorbent material for an embodiment of thepresent invention, where at least one component of a dry powderinhalation device comprises polyacetal, is a molecular sieve with a poresize of about 10 Angstroms. Inclusion of 1 to 10 grams of the molecularsieve, for example, supplied by AtoFina (Solihull, England) under thetrade name SILIPORITE, is a particular molecular sieve havingapplications as a sorbent material. Molecular sieves can also bepurchased from Linde, Air Products, etc. More detailed technicalinformation about molecular sieves and their industrial uses can befound in the Molecular Sieves: Unique Moisture and Odor-Taste ControlMaterial”, D. Hajdu, T. J. Dangieri and S. R. Dunne, TAPPI Polym.,Laminations Coat. Conf. (1999), Vol. 2, p. 655-662, which is herebyincorporated by reference herein in its entirety.

There are numerous ways in which a sorbent material can be incorporatedinto a pharmaceutical product of the present invention. For example, thesorbent material can be incorporated into a polymer mixture andmanufactured into a plastic component of a dry powder inhalation deviceof a pharmaceutical product of the present invention, or manufacturedinto plastic sheeting used in the packaging of the device. Furthermore,the sorbent material can be incorporated into a polymer mixture in thesame, or similar manner as desiccant polymer mixtures disclosed in U.S.Pat. Nos. 5,911,937; 3,245,946, 4,013,566, 4,407,897; 4,425,410;4,464,443; 5,078,909; and 4,792,484, which are hereby incorporated byreference herein in their entireties. Moreover, a sorbent material canbe incorporated into a stable pharmaceutical product of the presentinvention in an adhesive (e.g. a self-adhesive patch or tape), in thesame, or similar, manner as adhesive desiccants disclosed in U.S. Pat.No. 6,103,141, which is hereby incorporated by reference herein in itsentirety. The sorbent material can also be within a cavity in a drypowder inhalation device (i.e. housed in the device) of a stablepharmaceutical product of the present invention, or situated inside acap or body of a dry-powder inhaler. Furthermore, the sorbent materialcan be incorporated into a component of a dry powder inhalation device,such as a cap, body, or a portion thereof in the form of a polymermixture. The sorbent material can be affixed to a dry powder inhalationdevice of a stable pharmaceutical product of the present invention inthe form of an adhesive sticker/tape that comprises the sorbentmaterial. In another example, the sorbent material can be separate froma dry powder inhalation device in an enclosed volume within which thedevice is situated.

A sorbent material of a stable pharmaceutical product of the inventioncan also be in a porous sachet. Such a sachet need not be in a sealedpackage. However though, in a particular embodiment of the presentinvention, a porous sachet having the sorbent material is containedwithin a sealed package. Sorbent sachets are commercially available froma variety of suppliers, such as Sud-Chemie (Middlewich, England). Thesachet, with a “tea-bag” like appearance, is generally manufactured fromsynthetic fibers, such as polyamide or polyester fibers or blendsthereof. Commercially available materials suitable for making sorbentsachets include, for example, “GDT-II” from San-ei Corporation (Osaka,Japan), and “TYVEK” from Perfecseal (Londonderry N. Ireland U.K.).However, a suitable sachet may be in other convenient shapes orappearances, and be made from other permeable materials.

As used herein, the phrase “effective amount of a sorbent material”refers to the amount of an sorbent material sufficient to adsorb orabsorb (or a combination thereof) a substance that leaches from acomponent of a dry powder inhalation device of a stable pharmaceuticalproduct of the present invention, in order to reduce or eliminate theformation of adducts with R,R,-formoterol L-tartrate salt, and inparticular crystalline R,R-formoterol L-tartrate salt, of apharmaceutical composition of a stable pharmaceutical product of thepresent invention. In a particular embodiment, wherein a component ofthe dry powder inhalation device comprises polyacetal, the substancethat leaches from the component is formaldehyde. The effective amount ofsorbent material will depend on a number of factors, including the typeof sorbent material used, and the number of components of the dry powderinhalation device that leach the substance. One of ordinary skill in theart can readily determine the effective amount of sorbent material for astable pharmaceutical product of the present invention using routinelaboratory techniques.

Pharmaceutical Composition

As explained above, a pharmaceutical composition of a stablepharmaceutical product of the present invention comprises R,R-formoterolL-tartrate salt, particularly R,R-formoterol L-tartrate salt; andciclesonide.

A pharmaceutical composition of a stable pharmaceutical product of thepresent invention can also comprise a pharmaceutically acceptablecarrier. As used herein, the phrase “pharmaceutically acceptable” refersto molecular entities and compositions that are physiologicallytolerable and do not typically produce an allergic or similar untowardreaction, such as gastric upset, dizziness and the like. Particularly,as used herein, the phrase “pharmaceutically acceptable” means approvedby a regulatory agency of the Federal or a state government, or listedin the U.S. Pharmacopeia, or other generally recognized pharmacopeia foruse in animals, and more particularly in humans. The term “carrier”refers to a diluent, adjuvant, excipient, or vehicle with which anactive compound(s) is (are) administered. Examples of pharmaceuticalcarriers are described in “Remington's Pharmaceutical Sciences” by E. W.Martin.

A stable pharmaceutical product of the present invention comprises,inter alia, a pharmaceutical composition for pulmonary ad ministration,and may include diluents of various buffer content (e.g., Tris-HCl,acetate, phosphate), pH and ionic strength; additives such as detergentsand solubilizing agents (e.g., Tween 80, Polysorbate 80), anti-oxidants(e.g., ascorbic acid, sodium metabisulfite), preservatives (e.g.,Thimersol, benzyl alcohol) and bulking substances (e.g., lactose,mannitol); incorporation of the material into particulate preparationsof polymeric compounds such as polylactic acid, polyglycolic acid, etc.,or into liposomes. Hylauronic acid may also be used. Such compositionsmay influence the physical state, stability, rate of in vivo release.See, e.g., Remington's Pharmaceutical Sciences, 18th Ed. (1990, MackPublishing Co., Easton, Pa. 18042) pages 1435-1712, which are hereinincorporated by reference. The compositions may be prepared in liquidform, or may be in dried powder, such as lyophilized form.

Contemplated for use in the present invention are a wide variety of drypowder inhalation devices designed for pulmonary delivery of apharmaceutical composition comprising R,R-formoterol L-tartrate salt,particularly crystalline R,R-formoterol L-tartrate salt, andciclesonide, all of which are familiar to those skilled in the art.

Some specific examples of commercially available devices suitable forthe practice of the present invention are the SPINHALER powder inhaler,manufactured by Fisons Corp., Bedford, Mass., the AEROLIZER inhalerproduced by Novartis, and the ULTRAHALER device produced by AventisPharma, Ltd. to name only a few. Other examples of dry powder inhalationdevices having applications in a stable pharmaceutical product of thepresent invention include those described in U.S. Pat. No. 5,176,132 andU.S. Pat. No. 5,678,538, and U.S. Provisional Patent Application No.60/417,534, which are hereby incorporated by reference herein in theirentireties. In a particular embodiment, the dry powder inhalation deviceis the ULTRAHALER.

All dry powder inhalations presently available or subsequently developedrequire the use of formulations suitable for the dispensing of apharmaceutical composition comprising R,R-formoterol L-tartrate salt,particularly crystalline R,R-formoterol L-tartrate salt, andciclesonide. Typically, each formulation is specific to the type ofdevice employed, and may involve the use of an appropriate adjuvantand/or carrier useful in therapy.

A particular example of a pharmaceutically acceptable carrier havingapplications herein is a reducing sugar such as lactose, glucose,mannose, galactose, maltose, xylose, cellobiose, mellibiose,maltotriose, etc., as well as hydrates thereof, in amounts whichfacilitate dispersal of the powder from the device. As used herein, theterm “reducing sugar” refers to a carbohydrate that undergoes oxidationand is able to reduce a metal ion to a lower oxidation state. Inparticular, a reducing sugar having applications as a pharmaceuticallyacceptable carrier is lactose. More particularly, the reducing sugar islactose monohydrate. A particular grade of lactose having applicationshere is RESPITOSE ML001 (DMV, Veghel, The Netherlands). Moreover, areducing sugar having applications herein as a pharmaceuticallyacceptable carrier need not be micronised.

Naturally, the particle size of a pharmaceutically acceptable carrier ofa pharmaceutical composition of a stable pharmaceutical product of thepresent invention can vary. In an embodiment of the present inventionwhich further comprises a reducing sugar as a pharmaceutically effectivecarrier, the size of the particles can range from about 0.5 μm to about350 μm, from about 0.5 μm to about 315 μm, from about 0.5 μm to about150 μm, from about 0.5 μm to about 100 μm, from about 0.5 μm to about 45μm, from about 0.5 μm to about 25 μm, from about 0.5 μm to about 10 μm,from about 5 μm to about 350 μm, from about 5 μm to about 315 μm, fromabout 5 μm to about 150 μm, from about 5 μm to about 100 μm, from about5 μm to about 45 μm, from about 5 μm to about 25 μm, from about 5 μm toabout 10 μm, from about 10 μm to about 350 μm, from about 10 μm to about315 μm, from about 10 μm to about 150 μm, from about 10 μm to about 100μm, from about 10 μm to about 45 μm, from about 10 μm to about 25 μm,from about 25 μm to about 350 μm, from about 25 μm to about 315 μm, fromabout 25 μm to about 150 μm, from about 25 μm to about 100 μm, fromabout 25 μm to about 45 μm, from about 45 μm to about 350 μm, from about45 μm to about 315 μm, from about 45 μm to about 150 μm, from about 45μm to about 100 μm, from about 100 μm to about 350 μm from about 100 μmto about 315 μm, from about 100 μm to about 150 μm, from about 150 μm toabout 350 μm, from about 150 μm to about 315 μm, from about 315 μm toabout 350 μm. In a particular embodiment, the pharmaceuticallyacceptable carrier is non-micronised lactose monohydrate havingparticles of a mean particle size of about 41 μm.

The particle size of R,R-formoterol L-tartrate salt, and particularcrystalline R,R-formoterol L-tartrate salt of a pharmaceuticalcomposition, as well ciclesonide, can vary. For example, the particlesize of the R,R-formoterol L-tartrate, and in particular crystallineR,R-formoterol L-tartrate salt, can be about 0.1 μm to about 10 μm. In aparticular embodiment, about 95% of the particles have a particle sizeless than about 5 μm, for most effective delivery to the distal lung.

Furthermore, the ratio of pharmaceutically acceptable carrier toR,R-formoterol L-tartrate salt, particularly crystalline R,R-formoterolL-tartrate salt, can vary in a pharmaceutical composition of a stablepharmaceutical product of the present invention. In an embodiment of thepresent invention, the ratio is about 2969 μg to about 3016 μg ofpharmaceutically acceptable carrier per about 0.5 μg to about 4 μg ofR,R-formoterol L-tartrate salt, particularly crystalline R,R-formoterolL-tartrate. In a more particular embodiment, a pharmaceuticalcomposition comprises about 2969 μg to about 3016 μg of pharmaceuticallyacceptable carrier per about 1 μg to about 2 μg of R,R-formoterolL-tartrate salt, particularly crystalline R,R-formoterol L-tartratesalt; and in a still more particular embodiment, a pharmaceuticalcomposition comprises about 2969 μg to about 3016 μg of pharmaceuticallyacceptable carrier per about 1 μg of R,R-formoterol L-tartrate salt,particularly crystalline R,R-formoterol L-tartrate salt.

Generally, the amount of ciclesonide in a pharmaceutical composition ofa stable pharmaceutical product of the present invention should be insufficient quantity so that at a daily dose range of from 20 to 1600 μgcan be administered to a patient. Exemplary doses in connection withinvention comprise 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 320 μgof ciclesonide, and in particular, the dose comprises 40, 80, 160 or 320μg ciclesonide. The dose is preferably a daily dose and a pharmaceuticalcomposition of a stable pharmaceutical product of the present inventioncan be administered once or twice daily, particularly once daily. A oncedaily dose may be administered any time of the day, e.g. in the morningor preferably in the evening. The administration of a daily dose of inthe range of from 20 to 320 μg of ciclesonide is preferably part of acontinuous treatment regimen, preferably a treatment period of more thanone day, particularly preferably more than one week, e.g. a two weektreatment period, a one month treatment period, a one year treatmentperiod or a life long treatment period.

While there have been described and pointed out fundamental novelfeatures of the present invention as applied to particular embodimentsthereof, it will be understood that various omissions and substitutionsand changes, in the form and details of the packages, sorbent materialsand their location, pharmaceutical compositions, and methods, may bemade by those of ordinary skill in the art without departing from thespirit of the invention. For example, it is expressly intended that allcombinations of those elements and/or method steps, which performsubstantially the same function in substantially the same way to achievethe same results, are within the scope of the present invention.

The present invention may be better understood by reference to thefollowing non-limiting Example, which is provided as exemplary of theinvention. The following Example is presented in order to more fullyillustrate a particular embodiment of the present invention. It shouldin no way be construed, however, as limiting the broad scope of thepresent invention.

Example

A feasibility study to assess performance and stability of apharmaceutical composition comprising crystalline R,R-formoteroltartrate salt and ciclesonide in a dry powder inhaler in comparison witha pharmaceutical composition comprising R,S-formoterol fumaratedihydrate and ciclesonide has been performed. The particular inhalerused in this study was the ULTRAHALER produced by Aventis Pharma Ltd. UK

Preparation of Pharmaceutical ULTRAHALERs

Two ULTRAHALERS were prepared. One contained a pharmaceuticalcomposition comprising crystalline R,R-formoterol L-tartrate salt,ciclesonide, and non-micronized lactose monohydrate as apharmaceutically acceptable carrier. The other contained apharmaceutical composition comprising R,S-formoterol fumarate dihydrate,ciclesonide, and non-micronized lactose monohydrate as a pharmaceuticalcarrier. A method for producing such ULTRAHALERS is set forth below:

-   1. Deaggregate both lactose monohydrate and drug substances    (separately).-   2. Add the lactose monohydrate, ciclesonide and formoterol (either    crystalline R,R-formoterol L-tartrate salt or R,S-formoterol    fumarate dihydrate, depending upon which pharmaceutical product is    being produced) into the mixing drum.-   3. Mix the composition for approximately 7 minutes-   4. Fill the blend into a dry powder inhalation device    (ULTRAHALER-Aventis Pharma Ltd, UK) using a filling machine (e.g.    fill weight limits 2.5-2.7 g)-   5. after being filled, wrap the dry powder inhalation device with    molecular sieves inside a laminate foil overwrap (i.e. 12 micron    polyester/9 micron aluminum foil/50 micron polyethylene), using    conventional means.    Stability Testing

A blend of Ciclesonide (19.97 mg/g), crystalline R,R formoterolL-tartrate salt (0.3 mg/g) and non-micronized lactose monohydrate(979.70 mg/g) were blended in a tumble mixer for several minutes.Another blend of Ciclesonide (19.97 mg/g), R,S-formoterol fumaratedihydrate (0.3 mg/g) and non-micronized lactose monohydrate (979.70mg/g) was also blended for several minutes. Each blend was thenseparately filled into an Aventis ULTRAHALER device using a fillingmachine. The filled ULTRAHALER devices were then wrapped in an laminatefoil overwrap with a molecular sieve porous sachet (4 g of 10 Åmolecular sieves). Three wrapped ULTRAHALERs containing thepharmaceutical composition comprising crystalline R,R-formoterolL-tartrate salt were produced. One was stored at 40° Celsius and 75%relative humidity, another was stored at 25 degrees Celsius and 60%relative humidity and the third was stored at 4 degrees Celsius andambient humidity, each of which were stored for 2 months. An ULTRAHALERdevice containing a pharmaceutical composition comprising R,S-formoterolfumarate dihydrate was stored at 40 degrees Celsius and 75% relativehumidity, for 2 months The amount of degradation in the samples storedat these conditions were measured by HPLC using the following analyticalconditions:

Column: Hipersil BDS-C18, 5 μm particle size, 150 mm × 4.6 mm i.d.Column temperature: Ambient Mobile phase A 30% Ammonium Acetate (pH 8.0± 0.05), composition: 55% Water, 15% Acetonitrile Mobile phase B 300Ammonium Acetate (pH 8.0 ± 0.05): composition: 750 Acetonitrile GradientTime Table Time (min) % A % B 0 100 0 10 100 0 20 87 13 30 70 30 40 7030 40.1 0 100 53.0 0 100 53.1 100 0 Flow rate: 1.0 ml/minute Detection:250 nmResults:

The results of this stability test, graphically shown in FIG. 1, showthat at the initial crystalline R,R stability time point, threedegradents were identified at Relative Retention Times (RRT)=1.10,RRT=1.14 and RRT=1.55 at levels of 0.19, 0.14 and 0.16% area,respectively. During storage of the DPT's at 40 degrees Celsius and 75%relative humidity, 25 degrees Celsius and 60% relative humidity, and 4degrees Celsius and ambient humidity for 2 months, the levels of thedegradents increased consistently across the storage conditions with anadditional degradent being detected at RRT=0.42. This is in starkcontrast to the levels of degradation observed with the same productmanufactured using R,S formoterol fumarate dihydrate stored at 40degrees Celsius and 75% relative humidity, wherein impurities aredetected at different RRT's (RRT=0.93, RRT=1.35 and RRT=1.86). The totaldegradation of the R,S formoterol fumarate product is 2.29% areacompared to 0.67% area in the crystalline R,R formoterol tartrateproduct at the 2 months stability time point when stored at 40 degreesCelsius and 75% relative humidity, where the initially 0.49% area totaldegradation was detected. This data clearly demonstrates the increasedstability of the crystalline R,R-formoterol L-tartrate saltpharmaceutical product compared to the R,S formoterol fumarate product.

The present invention is not to be limited in scope by the specificembodiments described herein. Indeed, various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description and theaccompanying figures. Such modifications are intended to fall within thescope of the appended claims.

Various publications are cited herein, the disclosures of which areincorporated by reference in their entireties.

1. A method of reducing degradation of R,R-formoterol L-tartrate salt ina dry powder inhalation device, said method comprising providing apharmaceutical product which comprises: a) a dry powder inhalationdevice; b) an effective amount of a sorbent material; and c) apharmaceutical composition within said device comprising: (i)R,R-formoterol L-tartrate salt; and (ii) ciclesonide; and sealingcomponents a), b) and c) in a package having an enclosed volume withinwhich said device, said sorbent material and said pharmaceuticalcomposition are situated; wherein a component of said dry powderinhalation device leaches a substance that accumulates within saidsealed package causing degradation of said R,R-formoterol L-tartratesalt; wherein said sorbent material is selected from the groupconsisting of: a molecular sieve, activated clay, charcoal, activatedalumina, silica, a zeolite, a bauxite, and a mixture thereof; andwherein said sorbent material adsorbs or absorbs, or a combinationthereof, the substance that leaches so as to reduce or eliminate theformation of adducts with R,R-formoterol L-tartrate salt.
 2. The methodaccording to claim 1, wherein said R, R-formoterol L-tartrate salt iscrystalline R,R-formoterol L-tartrate salt.
 3. The method according toclaim 1, wherein said component of the dry powder inhalation devicecomprises polyacetal material, and said substance is formaldehyde. 4.The method according to claim 3, wherein said polyacetal metal ispolyoxymethylene.
 5. The method according to claim 1, wherein saidsorbent material is housed within said dry powder inhalation device. 6.The method according to claim 1, wherein said sorbent material is in aporous sachet.
 7. The method according to claim 1, wherein said sorbentmaterial is 10 Å molecular sieves.
 8. The method according to claim 1,wherein said pharmaceutical composition further comprises apharmaceutically acceptable carrier.
 9. The method according to claim 8,wherein said pharmaceutically acceptable carrier is a reducing sugar.10. The method according to claim 9, wherein said reducing sugar islactose monohydrate.
 11. The method according to claim 8, wherein saidpharmaceutical composition comprises about 2969 μg to about 3016 μg ofsaid pharmaceutically acceptable carrier per about 0.5 μg to about 4 μgof R,R-formoterol L-tartrate salt.
 12. The method according to claim 8,wherein said pharmaceutical composition comprises about 2969 μg to about3016 μg of said pharmaceutically acceptable carrier per about 1 μg toabout 2 μg of R,R-formoterol L-tartrate salt.
 13. The method accordingto claim 8, wherein said pharmaceutical composition comprises about 2969μg to about 3016 μg of said pharmaceutically acceptable carrier perabout 1 μg of R,R-formoterol L-tartrate salt.
 14. The method accordingto claim 9, wherein said reducing sugar is not micronised.
 15. Themethod according to claim 9, wherein said reducing sugar has a meanparticle size of about 41 μm.
 16. The method according to claim 9,wherein said reducing sugar is selected from the group consisting oflactose, lactose monohydrate, glucose, glucose monohydrate, mannose,galactose, maltose, maltose hydrate, xylose, cellobiose, mellibiose,maltotriose and combinations thereof.
 17. The method according to claim9, wherein said reducing sugar is lactose.
 18. The method according toclaim 8, wherein said pharmaceutically acceptable carrier isnon-micronized lactose monohydrate having a particle size of about 41μm.
 19. The method according to claim 1, wherein said sorbent materialis an effective amount of 10 Å sieves enclosed in a porous sachet. 20.The method according to claim 19, wherein said effective amount of 10 Åsieves is 4 g.
 21. The method according to claim 1, wherein said drypowder inhalation device comprises a multi-dose reservoir that containssaid pharmaceutical composition.
 22. The method according to claim 1,wherein said sorbent material is incorporated into a polymer mixture andmanufactured into a component of said dry powder inhalation device. 23.The method according to claim 1, wherein said sorbent material isincorporated into plastic sheeting used in packaging said dry powderinhalation device.
 24. The method according to claim 1, wherein saidsorbent material is incorporated into an adhesive.
 25. The methodaccording to claim 1, wherein said R,R-formoterol L-tartrate salt has aparticle size of about 0.1 μm to about 10 μm.
 26. The method accordingto claim 1, wherein greater than about 95% of said R,R-formoterolL-tartrate salt has a particle size of less than about 5 μm.
 27. Themethod according to claim 1, wherein said sealed package is made ofmetal, glass, or plastic, and has a configuration selected from thegroup consisting of a bottle, a bag, a drum box, and an irregularlyshaped container.
 28. The method according to claim 1, wherein saidsealed package is made of plastic.
 29. The method according to claim 1,wherein said sealed package is a flexible laminate comprising an innerlayer, a barrier layer, and an outer layer, wherein said barrier layeris located between said inner layer and said outer layer.
 30. The methodaccording to claim 29, wherein said inner layer is polyethylene, saidbarrier layer is a metal foil, wherein said metal is selected from thegroup consisting of aluminum, copper, steel, zinc, tin, magnesium, andan amalgam thereof, and said outer layer comprises polyester or paper.31. The method according to claim 30, wherein said flexible laminatecomprises a 12 micron polyester outer layer, a 9 micron aluminum foilbarrier layer, and a 50 micron polyethylene inner layer.
 32. The methodaccording to claim 1, wherein said sealed package is hermetically sealedusing heat-sealing, glue, a weld, brazing said sealed package, amechanical closure or clamp, or compression of said sealed package.